List of publications for October 22, 2022
Shared brain and genetic architectures between mental health and physical activity
(2022) Translational Psychiatry, 12 (1), art. no. 428, .
Zhang, W.a , Paul, S.E.b , Winkler, A.c , Bogdan, R.b , Bijsterbosch, J.D.a
a Radiology Department, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
c National Institute of Mental Health/National Institutes of Health, Rockville, MD, United States
Abstract
Physical activity is correlated with, and effectively treats various forms of psychopathology. However, whether biological correlates of physical activity and psychopathology are shared remains unclear. Here, we examined the extent to which the neural and genetic architecture of physical activity and mental health are shared. Using data from the UK Biobank (N = 6389), we applied canonical correlation analysis to estimate associations between the amplitude and connectivity strength of subnetworks of three major neurocognitive networks (default mode, DMN; salience, SN; central executive networks, CEN) with accelerometer-derived measures of physical activity and self-reported mental health measures (primarily of depression, anxiety disorders, neuroticism, subjective well-being, and risk-taking behaviors). We estimated the genetic correlation between mental health and physical activity measures, as well as putative causal relationships by applying linkage disequilibrium score regression, genomic structural equational modeling, and latent causal variable analysis to genome-wide association summary statistics (GWAS N = 91,105–500,199). Physical activity and mental health were associated with connectivity strength and amplitude of the DMN, SN, and CEN (r’s ≥ 0.12, p’s < 0.048). These neural correlates exhibited highly similar loading patterns across mental health and physical activity models even when accounting for their shared variance. This suggests a largely shared brain network architecture between mental health and physical activity. Mental health and physical activity (including sleep) were also genetically correlated (|rg| = 0.085–0.121), but we found no evidence for causal relationships between them. Collectively, our findings provide empirical evidence that mental health and physical activity have shared brain and genetic architectures and suggest potential candidate subnetworks for future studies on brain mechanisms underlying beneficial effects of physical activity on mental health. © 2022, The Author(s).
Funding details
National Institutes of HealthNIH
National Institute of Mental HealthNIMHR01 MH128286
National Institute of Neurological Disorders and StrokeNINDSR34 NS118618
McDonnell Center for Systems Neuroscience1 F31 AA029934-01
Document Type: Article
Publication Stage: Final
Source: Scopus
Blood–brain barrier opening in a large animal model using closed-loop microbubble cavitation-based feedback control of focused ultrasound sonication
(2022) Scientific Reports, 12 (1), art. no. 16147, .
Chien, C.-Y.a , Xu, L.a , Pacia, C.P.a , Yue, Y.a , Chen, H.a b
a Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, United States
b Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park Ave., Saint Louis, MO 63108, United States
Abstract
Focused ultrasound (FUS) in combination with microbubbles has been established as a promising technique for noninvasive and localized Blood–brain barrier (BBB) opening. Real-time passive cavitation detection (PCD)-based feedback control of the FUS sonication is critical to ensure effective BBB opening without causing hemorrhage. This study evaluated the performance of a closed-loop feedback controller in a porcine model. Calibration of the baseline cavitation level was performed for each targeted brain location by a FUS sonication in the presence of intravenously injected microbubbles at a low acoustic pressure without inducing BBB opening. The target cavitation level (TCL) was defined for each target based on the baseline cavitation level. FUS treatment was then performed under real-time PCD-based feedback controller to maintain the cavitation level at the TCL. After FUS treatment, contrast-enhanced MRI and ex vivo histological staining were performed to evaluate the BBB permeability and safety. Safe and effective BBB opening was achieved with the BBB opening volume increased from 3.8 ± 0.7 to 53.6 ± 23.3 mm3 as the TCL was increased from 0.25 to 1 dB. This study validated that effective and safe FUS-induced BBB opening in a large animal model can be achieved with closed-loop feedback control of the FUS sonication. © 2022, The Author(s).
Funding details
National Institutes of HealthNIHR01EB027223, R01EB030102, R01MH116981
Document Type: Article
Publication Stage: Final
Source: Scopus
The effect of A1 and A2 reactive astrocyte expression on hydrocephalus shunt failure
(2022) Fluids and Barriers of the CNS, 19 (1), art. no. 78, .
Khodadadei, F.a , Arshad, R.b , Morales, D.M.c , Gluski, J.d , Marupudi, N.I.d , McAllister, J.P., IIc , Limbrick, D.D., Jr.c , Harris, C.A.a d e
a Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI, United States
b School of Medicine, Wayne State University, Detroit, MI, United States
c Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, United States
e Department of Biomedical Engineering, Wayne State University, Detroit, MI, United States
Abstract
Background: The composition of tissue obstructing neuroprosthetic devices is largely composed of inflammatory cells with a significant astrocyte component. In a first-of-its-kind study, we profile the astrocyte phenotypes present on hydrocephalus shunts. Methods: qPCR and RNA in-situ hybridization were used to quantify pro-inflammatory (A1) and anti-inflammatory (A2) reactive astrocyte phenotypes by analyzing C3 and EMP1 genes, respectively. Additionally, CSF cytokine levels were quantified using ELISA. In an in vitro model of astrocyte growth on shunts, different cytokines were used to prevent the activation of resting astrocytes into the A1 and A2 phenotypes. Obstructed and non-obstructed shunts were characterized based on the degree of actual tissue blockage on the shunt surface instead of clinical diagnosis. Results: The results showed a heterogeneous population of A1 and A2 reactive astrocytes on the shunts with obstructed shunts having a significantly higher proportion of A2 astrocytes compared to non-obstructed shunts. In addition, the pro-A2 cytokine IL-6 inducing proliferation of astrocytes was found at higher concentrations among CSF from obstructed samples. Consequently, in the in vitro model of astrocyte growth on shunts, cytokine neutralizing antibodies were used to prevent activation of resting astrocytes into the A1 and A2 phenotypes which resulted in a significant reduction in both A1 and A2 growth. Conclusions: Therefore, targeting cytokines involved with astrocyte A1 and A2 activation is a promising intervention aimed to prevent shunt obstruction. © 2022, The Author(s).
Author Keywords
A1 and A2 reactive astrocyte phenotype; Glial Scar; Hydrocephalus; Neuroprosthetic device failure; Targeted drug delivery
Funding details
Wayne State UniversityWSU
Hydrocephalus AssociationHA
Document Type: Article
Publication Stage: Final
Source: Scopus
Association of Pretreatment Hippocampal Volume With Neurocognitive Function in Patients Treated With Hippocampal Avoidance Whole Brain Radiation Therapy for Brain Metastases: Secondary Analysis of NRG Oncology/RTOG 0933
(2022) Advances in Radiation Oncology, 7 (6), art. no. 100859, .
Abraham, C.D.a b , Pugh, S.L.c , Bovi, J.A.d , Gondi, V.e , Mehta, M.P.f , Benzinger, T.a , Owen, C.J.a , Lo, S.S.g , Kundapur, V.h , Brown, P.D.i , Sun, A.Y.j , Howard, S.P.k , DeNittis, A.S.l , Robinson, C.G.a , Kachnic, L.A.m
a Washington University School of Medicine, Saint Louis, Missouri
b Barnes-Jewish Hospital, Saint Louis, Missouri
c NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania
d Froedtert and the Medical College of Wisconsin, Milwaukee, WI, United States
e Northwestern Medicine Cancer, Warrenville, IL, United States
f Miami Cancer Institute, Miami, Florida
g University of Washington Medical Center, Seattle, WA, United States
h Saskatoon Cancer Centre, Saskatoon, SK, Canada
i Mayo Clinic, Rochester, Minnesota
j University Health Network–Princess Margaret Hospital, Toronto, ON, Canada
k University of Wisconsin Hospital and Clinics, Madison, WI, United States
l MainLine Health NCORP, WynnewoodPennsylvania
m Columbia University, New York, New York
Abstract
Purpose: Hippocampal volume (HV) is an established predicting factor for neurocognitive function (NCF) in neurodegenerative disease. Whether the same phenomenon exists with hippocampal-avoidant whole brain radiation therapy is not known; therefore, we assessed the association of baseline HV with NCF among patients enrolled on RTOG 0933. Methods and Materials: Hippocampal volume and total brain volume were calculated from the radiation therapy plan. Hippocampal volume was correlated with baseline and 4-month NCF scores (Hopkins Verbal Learning Test–Revised [HVLT-R] Total Recall [TR], Immediate Recognition, and Delayed Recall [DR]) using Pearson correlation. Deterioration in NCF was defined per the primary endpoint of RTOG 0933(mean 4-month relative decline in HVLT-R DR). Comparisons between patients with deteriorated and nondeteriorated NCF were made using the Wilcoxon test. Results: Forty-two patients were evaluable. The median age was 56.5 years (range, 28-83 years), and 81% had a class II recursive partitioning analysis. The median total, right, and left HVs were 5.4 cm3 (range, 1.9-7.4 cm3), 2.8 cm3 (range, 0.9-4.0 cm3), and 2.7 cm3 (range, 1.0-3.7 cm3), respectively. The median total brain volume was 1343 cm3 (range, 1120.5-1738.8 cm3). For all measures of corrected HV, increasing HV was associated with higher baseline HVLT-R TR and DR scores (ρ: range, 0.35-0.40; P-value range,. 009-.024) and 4-month TR and DR scores (ρ: range, 0.29-0.40; P-value range,. 009-.04), with the exception of right HV and 4-month DR scores (ρ: 0.29; P = .059). There was no significant association between HV and NCF change between baseline and 4 months. Fourteen patients (33.3%) developed NCF deterioration per the primary endpoint of RTOG 0933. There was no significant difference in HV between patients with deteriorated and nondeteriorated NCF, although in all instances, patients with deteriorated NCF had numerically lower HV. Conclusions: Larger HV was positively associated with improved performance on baseline and 4-month HVLT-R TR and DR scores in patients with brain metastases undergoing hippocampal-avoidant whole brain radiation therapy but was not associated with a change in NCF. © 2021 The Authors
Funding details
National Cancer InstituteNCI
Merck
Roche
Biogen
Elekta
Document Type: Article
Publication Stage: Final
Source: Scopus
A bioresorbable peripheral nerve stimulator for electronic pain block
(2022) Science Advances, 8 (40), p. eabp9169.
Lee, G.a b , Ray, E.c d , Yoon, H.-J.a , Genovese, S.d , Choi, Y.S.a , Lee, M.-K.a , Şahin, S.a e , Yan, Y.d , Ahn, H.-Y.a , Bandodkar, A.J.f g , Kim, J.a , Park, M.a , Ryu, H.h , Kwak, S.S.i , Jung, Y.H.j , Odabas, A.d k , Khandpur, U.d , Ray, W.Z.c d , MacEwan, M.R.c d , Rogers, J.A.a l m n o
a Northwestern University, Evanston, IL 60208, United States
b Precision Biology Research Center, Sungkyunkwan University, Suwon, 16419, South Korea
c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
d Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
e Department of Bioengineering, Bilecik Şeyh Edebali UniversityBilecik 11230, Turkey
f Department of Electrical and Computer Engineering, North Carolina State University, Raleigh, United States
g Center for Advanced Self-Powered Systems of Integrated Sensors and Technologies (ASSIST), North Carolina State University, Raleigh, United States
h Department of Advanced Materials Engineering, Chung-Ang University, Anseong, 17546, South Korea
i Center for Bionics, Biomedical Research Division, Korea Institute of Science and TechnologySeoul 02792, South Korea
j Department of Electronic Engineering, Hanyang UniversitySeoul 04763, South Korea
k Department of Internal Medicine, Stanford University Medical Center, Stanford, CA 94305, USA
l Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, United States
m Department of Mechanical Engineering, Northwestern University, Evanston, IL 60208, United States
n Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, United States
o Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
Abstract
Local electrical stimulation of peripheral nerves can block the propagation of action potentials, as an attractive alternative to pharmacological agents for the treatment of acute pain. Traditional hardware for such purposes, however, involves interfaces that can damage nerve tissue and, when used for temporary pain relief, that impose costs and risks due to requirements for surgical extraction after a period of need. Here, we introduce a bioresorbable nerve stimulator that enables electrical nerve block and associated pain mitigation without these drawbacks. This platform combines a collection of bioresorbable materials in architectures that support stable blocking with minimal adverse mechanical, electrical, or biochemical effects. Optimized designs ensure that the device disappears harmlessly in the body after a desired period of use. Studies in live animal models illustrate capabilities for complete nerve block and other key features of the technology. In certain clinically relevant scenarios, such approaches may reduce or eliminate the need for use of highly addictive drugs such as opioids.
Document Type: Article
Publication Stage: Final
Source: Scopus
A non-canonical retina-ipRGCs-SCN-PVT visual pathway for mediating contagious itch behavior
(2022) Cell Reports, 41 (1), art. no. 111444, .
Gao, F.a b , Ma, J.a b , Yu, Y.-Q.a b c , Gao, X.-F.a b , Bai, Y.a d , Sun, Y.a d , Liu, J.a b , Liu, X.a b , Barry, D.M.a b , Wilhelm, S.a b , Piccinni-Ash, T.a b , Wang, N.a b , Liu, D.a b g , Ross, R.A.e , Hao, Y.a b , Huang, X.f , Jia, J.-J.a b , Yang, Q.a b , Zheng, H.f , van Nispen, J.a b , Chen, J.c , Li, H.d , Zhang, J.f , Li, Y.-Q.d , Chen, Z.-F.a b
a Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
b Departments of Anesthesiology, Medicine, Psychiatry and, Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Institute for Biomedical Sciences of Pain, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, China
d Department of Anatomy, Histology and Embryology & K.K. Leung Brain Research Centre, Fourth Military Medical University, Xi’an, 710032, China
e Department of Neuroscience, Psychiatry and Medicine, Albert Einstein College of Medicine Rose F. Kennedy Center, Bronx, NY, United States
f Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science and Institute for Medical and Engineering Innovation, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China
g Department of Pain Management, the State Key Clinical Specialty in Pain Medicine, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China
Abstract
Contagious itch behavior informs conspecifics of adverse environment and is crucial for the survival of social animals. Gastrin-releasing peptide (GRP) and its receptor (GRPR) in the suprachiasmatic nucleus (SCN) of the hypothalamus mediates contagious itch behavior in mice. Here, we show that intrinsically photosensitive retina ganglion cells (ipRGCs) convey visual itch information, independently of melanopsin, from the retina to GRP neurons via PACAP-PAC1R signaling. Moreover, GRPR neurons relay itch information to the paraventricular nucleus of the thalamus (PVT). Surprisingly, neither the visual cortex nor superior colliculus is involved in contagious itch. In vivo calcium imaging and extracellular recordings reveal contagious itch-specific neural dynamics of GRPR neurons. Thus, we propose that the retina-ipRGC-SCN-PVT pathway constitutes a previously unknown visual pathway that probably evolved for motion vision that encodes salient environmental cues and enables animals to imitate behaviors of conspecifics as an anticipatory mechanism to cope with adverse conditions. © 2022 The Author(s)
Author Keywords
contagious itch behavior; CP: Neuroscience; GRP; GRPR; ipRGCs; itch stimuli; neural dynamics; PACAP; SCN; scratching motion; stress
Funding details
National Institutes of HealthNIH1R01AR056318–06, R01 DA037261-01A1, R01NS094344
Document Type: Article
Publication Stage: Final
Source: Scopus
Evaluating brain damage in multiple sclerosis with simultaneous multi-angular-relaxometry of tissue
(2022) Annals of Clinical and Translational Neurology, 9 (10), pp. 1514-1527.
Xiang, B.a , Wen, J.a , Schmidt, R.E.b , Sukstanskii, A.L.a , Mamah, D.c , Yablonskiy, D.A.a , Cross, A.H.d
a Department of Radiology, Washington University, St. Louis, MO 63110, United States
b Department of Pathology, Washington University, St. Louis, MO 63110, United States
c Department of Psychiatry, Washington University, St. Louis, MO 63110, United States
d Department of Neurology, Washington University, St. Louis, MO 63110, United States
Abstract
Objective: Multiple sclerosis (MS) is a common demyelinating central nervous system disease. MRI methods that can quantify myelin loss are needed for trials of putative remyelinating agents. Quantitative magnetization transfer MRI introduced the macromolecule proton fraction (MPF), which correlates with myelin concentration. We developed an alternative approach, Simultaneous-Multi-Angular-Relaxometry-of-Tissue (SMART) MRI, to generate MPF. Our objective was to test SMART-derived MPF metric as a potential imaging biomarker of demyelination. Methods: Twenty healthy control (HC), 11 relapsing–remitting MS (RRMS), 22 progressive MS (PMS), and one subject with a biopsied tumefactive demyelinating lesion were scanned at 3T using SMART MRI. SMART-derived MPF metric was determined in normal-appearing cortical gray matter (NAGM), normal-appearing subcortical white matter (NAWM), and demyelinating lesions. MPF metric was evaluated for correlations with physical and cognitive test scores. Comparisons were made between HC and MS and between MS subtypes. Furthermore, correlations were determined between MPF and neuropathology in the biopsied person. Results: SMART-derived MPF in NAGM and NAWM were lower in MS than HC (p < 0.001). MPF in NAGM, NAWM and lesions differentiated RRMS from PMS (p < 0.01, p < 0.001, p < 0.001, respectively), whereas lesion volumes did not. MPF in NAGM, NAWM and lesions correlated with the Expanded Disability Status Scale (p < 0.01, p < 0.001, p < 0.001, respectively) and nine-hole peg test (p < 0.001, p < 0.001, p < 0.01, respectively). MPF was lower in the histopathologically confirmed inflammatory demyelinating lesion than the contralateral NAWM and increased in the biopsied lesion over time, mirroring improved clinical performance. Interpretation: SMART-derived MPF metric holds potential as a quantitative imaging biomarker of demyelination and remyelination. © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
National Institutes of HealthNIHR01 AG054513
National Multiple Sclerosis SocietyNMSSFG-1908-34882
Conrad N. Hilton FoundationCNHF20140257
Bristol-Myers SquibbBMS
EMD Serono
Foundation for Barnes-Jewish HospitalFBJH
Horizon Pharma
Greenwich Biosciences
Document Type: Article
Publication Stage: Final
Source: Scopus
Herpes simplex virus and rates of cognitive decline or whole brain atrophy in the Dominantly Inherited Alzheimer Network
(2022) Annals of Clinical and Translational Neurology, .
Warren-Gash, C.a , Cadogan, S.L.a , Nicholas, J.M.b , Breuer, J.M.c d , Shah, D.d , Pearce, N.b , Shiekh, S.a , Smeeth, L.a , Farlow, M.R.e , Mori, H.f , Gordon, B.A.g , Nuebling, G.h i , McDade, E.j , Bateman, R.J.j , Schofield, P.R.k l , Lee, J.-H.m , Morris, J.C.j , Cash, D.M.n o , Fox, N.C.o p , Ridha, B.H.o p , Rossor, M.N.o p , for the Dominantly Inherited Alzheimer Networkq
a Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
b Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, United Kingdom
c Institute of Child Health, University College London, Gower Street, London, WC1E 6BT, United Kingdom
d Virology Department, Great Ormond Street Hospital, London, United Kingdom
e Indiana University School of Medicine, Indianapolis, IN, United States
f Department of Clinical Neuroscience, Osaka Metropolitan University Medical School, Sutoku University, Osaka, Japan
g Department of Radiology, Washington University School of Medicine in St LouisMO, United States
h German Center for Neurodegenerative Diseases, Site Munich, Germany
i Department of Neurology, Ludwig-Maximilians University, Munich, Germany
j Department of Neurology, Washington University School of Medicine, St. Louis, United States
k Neuroscience Research Australia, Sydney, NSW, Australia
l School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
m Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
n UK Dementia Research Institute, University College London, London, United Kingdom
o Dementia Research Centre, Institute of Neurology, University College London, Queen Square, London, United Kingdom
p NIHR University College London Hospitals Biomedical Research Centre, London, United Kingdom
Abstract
Objective: To investigate whether herpes simplex virus type 1 (HSV-1) infection was associated with rates of cognitive decline or whole brain atrophy among individuals from the Dominantly Inherited Alzheimer Network (DIAN). Methods: Among two subsets of the DIAN cohort (age range 19.6–66.6 years; median follow-up 3.0 years) we examined (i) rate of cognitive decline (N = 164) using change in mini-mental state examination (MMSE) score, (ii) rate of whole brain atrophy (N = 149), derived from serial MR imaging, calculated using the boundary shift integral (BSI) method. HSV-1 antibodies were assayed in baseline sera collected from 2009–2015. Linear mixed-effects models were used to compare outcomes by HSV-1 seropositivity and high HSV-1 IgG titres/IgM status. Results: There was no association between baseline HSV-1 seropositivity and rates of cognitive decline or whole brain atrophy. Having high HSV-1 IgG titres/IgM was associated with a slightly greater decline in MMSE points per year (difference in slope − 0.365, 95% CI: −0.958 to −0.072), but not with rate of whole brain atrophy. Symptomatic mutation carriers declined fastest on both MMSE and BSI measures, however, this was not influenced by HSV-1. Among asymptomatic mutation carriers, rates of decline on MMSE and BSI were slightly greater among those who were HSV-1 seronegative. Among mutation-negative individuals, no differences were seen by HSV-1. Stratifying by APOE4 status yielded inconsistent results. Interpretation: We found no evidence for a major role of HSV-1, measured by serum antibodies, in cognitive decline or whole brain atrophy among individuals at high risk of early-onset AD. © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
NF‐SI‐0512‐10033
National Institutes of HealthNIH
National Institute on AgingNIA
Alzheimer’s AssociationAA
Queen Mary University of LondonQMUL
Fondation Brain Canada
Japan Agency for Medical Research and DevelopmentAMED17929884
Schizophrenia Research FundSRF
Wellcome TrustWT201440/Z/16/Z
Australasian Neuroscience SocietyANSP01AG003991, P01AG026276, P30 AG066444
Canadian Institutes of Health ResearchIRSC
Fonds de Recherche du Québec – SantéFRQS
Medical Research CouncilMRCMR/L023784/2, U19AG032438
National Institute for Health and Care ResearchNIHR
Alzheimer’s Society
Multiple Sclerosis SocietyMS Society
University of Warwick
Imperial College London
University of Bristol
Alzheimer’s Research UKARUK
Korea Health Industry Development InstituteKHIDI
Instituto de Salud Carlos IIIISCIII
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Strategic Research CouncilRSF
NSW Health
UCLH Biomedical Research CentreNIHR BRC
Fleni
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A new look at cognitive functioning in pediatric MS
(2022) Multiple Sclerosis Journal, .
Krupp, L.B.a , Waubant, E.b , Waltz, M.c , Casper, T.C.c , Belman, A.a , Wheeler, Y.d , Ness, J.d , Graves, J.e , Gorman, M.f , Benson, L.f , Mar, S.g , Goyal, M.g , Schreiner, T.h , Weinstock-Guttman, B.i , Rodriguez, M.j , Tillema, J.-M.j , Lotze, T.k , Aaen, G.l , Rensel, M.m , Rose, J.c , Chitinis, T.n , George, A.a , Charvet, L.E.a , and the US Network of Pediatric MS Centerso
a Multiple Sclerosis Comprehensive Care Center, Department of Neurology, NYU Langone Health, New York, NY, United States
b Pediatric Multiple Sclerosis Center, University of California San Francisco, San Francisco, CA, United States
c Data Coordinating and Analysis Center, The University of Utah, Salt Lake City, UT, United States
d Center for Pediatric-Onset Demyelinating Disease, The University of Alabama at Birmingham, Birmingham, AL, United States
e Pediatric Multiple Sclerosis Center, University of California San Diego, San Diego, CA, United States
f Pediatric Multiple Sclerosis and Related Disorders Program at Boston Children’s Hospital, Boston, MA, United States
g Washington University in St. Louis, St. Louis, MO, United States
h Rocky Mountain Multiple Sclerosis Center, Children’s Hospital Colorado, University of Colorado Denver, Aurora, CO, United States
i Jacobs Pediatric Multiple Sclerosis Center, State University of New York at Buffalo, Buffalo, NY, United States
j Mayo Clinic Pediatric Multiple Sclerosis Center, Mayo Clinic, Rochester, MN, United States
k The Blue Bird Circle Clinic for Multiple Sclerosis, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States
l Pediatric Multiple Sclerosis Center, Loma Linda University Children’s Hospital, Loma Linda, CA, United States
m Cleveland Clinic Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, United States
n Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital, Boston, MA, United States
Abstract
Objective: Cognitive involvement in pediatric multiple sclerosis (MS) relative to adult MS is less defined. This study advances our understanding by measuring cognitive performances in pediatric MS, adult MS, and pediatric healthy controls. Methods: Consecutive relapsing pediatric MS participants from the United States Network of Pediatric MS Centers were compared with pediatric healthy controls and adults with relapsing MS. Participants were compared on two screening batteries: the Brief International Cognitive Assessment for MS and the Cogstate Brief Battery. Results were transformed to age-normative z scores. Results: The pediatric groups (MS vs. Healthy Controls) did not differ on either battery’s composite mean score or individual test scores (ps > 0.32), nor in the proportions impaired on either battery, Brief International Cognitive Assessment for MS (26% vs. 24%, p = 0.83); Cogstate Brief Battery (26% vs. 32%, p = 0.41). The pediatric versus adult MS group even after controlling for differences in disease duration performed better on the Brief International Cognition Assessment for MS composite (p = 0.03), Symbol Digit Modalities Test (p = 0.02), Rey Auditory Verbal Learning Test (p = 0.01), and Cogstate choice reaction time (p < 0.001). Conclusion: Pediatric MS patients do not differ from healthy pediatric controls on cognitive screens but perform better than adults with MS. © The Author(s), 2022.
Author Keywords
adult MS; BICAMS; cognition; cognitive screening; Cogstate; Pediatric MS
Funding details
National Institutes of HealthNIH
U.S. Department of DefenseDOD
National Multiple Sclerosis SocietyNMSSHC-1509-06233, RG150705285
Pfizer
Novartis
Roche
Biogen
Patient-Centered Outcomes Research InstitutePCORI
Teva Pharmaceutical Industries
Biogen Idec
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Cognitive Development in Lambdoid Craniosynostosis: A Systematic Review and Meta-Analysis
(2022) Cleft Palate-Craniofacial Journal, .
Chiang, S.N.a , Fotouhi, A.R.a , Doering, M.M.b , Skolnick, G.B.a , Naidoo, S.D.a , Strahle, J.M.c , McEvoy, S.D.c , Patel, K.B.a
a Department of Surgery, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Bernard Becker Medical Library, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Objective: Lambdoid craniosynostosis affects approximately 1 in 33 000 live births per year, and surgical correction is often sought in order to achieve normocephaly and allow for adequate brain growth. However, the effects of lambdoid synostosis and its treatment on cognitive development are unknown. Design: Systematic review and meta-analysis. Patients, Participants: A systematic review of Ovid Medline, Embase, Web of Science, Scopus, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov was conducted in January 2022. Included studies assessed cognitive development of patients with nonsyndromic unilateral lambdoid craniosynostosis. Main Outcome Measures: Results of developmental tests were compared to normative data or controls to generate Hedges’ g for meta-analysis. Results: Nine studies met the inclusion criteria. Meta-analysis of 3 studies describing general cognition showed that cases scored significantly lower than their peers, but within 1 standard deviation (g = 0.37, 95% CI [−0.64, −0.10], P =.01). Meta-analysis of verbal and psychomotor development showed no significant differences in children with lambdoid synostosis. Studies were of fair quality and had moderate-to-high heterogeneity. Conclusions: Patients with lambdoid craniosynostosis may score slightly below average on tests of general cognition in comparison to normal controls, but results in other domains are variable. Analyses were limited by small sample sizes. Multidisciplinary care and involvement of a child psychologist may be helpful in identifying areas of concern and providing adequate scholastic support. Further research recruiting larger cohorts will be necessary to confirm these findings and extend them to other developmental domains such as attention and executive function. © 2022, American Cleft Palate-Craniofacial Association.
Author Keywords
language development; mental development; psychomotor development; speech development
Funding details
Washington University School of Medicine in St. LouisWUSM
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
MOG and AQP4 Antibodies among Children with Multiple Sclerosis and Controls
(2022) Annals of Neurology, .
Gaudioso, C.M.a , Mar, S.a , Casper, T.C.b , Codden, R.b , Nguyen, A.c , Aaen, G.d , Benson, L.e , Chitnis, T.f , Francisco, C.g , Gorman, M.P.e , Goyal, M.S.a , Graves, J.h , Greenberg, B.M.i , Hart, J.g , Krupp, L.j , Lotze, T.k , Narula, S.l , Pittock, S.J.c , Rensel, M.m , Rodriguez, M.n , Rose, J.o , Schreiner, T.p , Tillema, J.-M.n , Waldman, A.l , Weinstock-Guttman, B.q , Wheeler, Y.r , Waubant, E.g , Flanagan, E.P.c , United States Network of Pediatric Multiple Sclerosis Centerss
a Department of Neurology, Washington University Pediatric MS and Other Demyelinating Disease Center, St. Louis, MO, United States
b Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
c Department of Neurology and Laboratory Medicine and Pathology and the Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, MN, United States
d Department of Pediatrics, Pediatric Multiple Sclerosis Center at Loma Linda University Children’s Hospital, Loma Linda University, Loma Linda, CA, United States
e Department of Neurology, Pediatric Multiple Sclerosis and Related Disorders Program at Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
f Partners Pediatric MS Center, Massachusetts General Hospital, Boston, MA, United States
g Department of Neurology, UCSF Regional Pediatric MS Center, San Francisco, CA, United States
h Department of Neurology, University of California San Diego Health, Rady Children’s Hospital San Diego, San Diego, CA, United States
i Department of Neurology, University of Texas Southwestern and Children’s Health, Dallas, TX, United States
j Department of Neurology, New York University, Pediatric MS Center, Neurology, New York, NY, United States
k Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States
l Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
m Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, United States
n Mayo Clinic Pediatric MS Center, Mayo Clinic, Rochester, MN, United States
o Department of Neurology, University of Utah, Salt Lake City, UT, United States
p Rocky Mountain MS Center, Children’s Hospital Colorado, University of Colorado, Aurora, CO, United States
q Department of Neurology, The Pediatric MS Center at the Jacobs Neurological Institute, State University of New York at Buffalo, Buffalo, NY, United States
r Center for Pediatric-Onset Demyelinating Disease at the Children’s of Alabama, University of Alabama, Birmingham, AL, United States
Abstract
Objective: The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among patients with pediatric-onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG-IgG-associated disease (MOGAD), and identify clinical features associated with final diagnosis. Methods: Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case–control study on POMS risk factors. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays. Results: AQP4-IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG-IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty-five of 30 patients positive with MOG-IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re-review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p = 0.044), younger age (mean = 8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p = 0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p = 0.002), serum Epstein–Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001). Interpretation: MOG-IgG and AQP4-IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4-IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2022. © 2022 American Neurological Association.
Funding details
National Institute of Neurological Disorders and StrokeNINDS1R01NS071463, R01NS113828, S1‐1808‐32326
National Multiple Sclerosis SocietyNMSS
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Comparison of plasma and CSF biomarkers in predicting cognitive decline
(2022) Annals of Clinical and Translational Neurology, .
Aschenbrenner, A.J.a b , Li, Y.b c , Henson, R.L.a b , Volluz, K.a b , Hassenstab, J.a b , Verghese, P.d , West, T.d , Meyer, M.R.d , Kirmess, K.M.d , Fagan, A.M.a b e , Xiong, C.b c , Holtzman, D.a b e , Morris, J.C.a b e , Bateman, R.J.a b e , Schindler, S.E.a b
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
c Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
d C2N Diagnostics, St. Louis, MO, United States
e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Objectives: Concentrations of amyloid-β peptides (Aβ42/Aβ40) and neurofilament light (NfL) can be measured in plasma or cerebrospinal fluid (CSF) and are associated with Alzheimer’s disease brain pathology and cognitive impairment. This study directly compared plasma and CSF measures of Aβ42/Aβ40 and NfL as predictors of cognitive decline. Methods: Participants were 65 years or older and cognitively normal at baseline with at least one follow-up cognitive assessment. Analytes were measured with the following types of assays: plasma Aβ42/Aβ40, immunoprecipitation-mass spectrometry; plasma NfL, Simoa; CSF Aβ42/Aβ40, automated immunoassay; CSF NfL plate-based immunoassay. Mixed effects models evaluated the global cognitive composite score over a maximum of 6 years as predicted by the fluid biomarkers. Results: Analyses included 371 cognitively normal participants, aged 72.7 ± 5.2 years (mean ± standard deviation) with an average length of follow-up of 3.9 ± 1.6 years. Standardized concentrations of biomarkers were associated with annualized cognitive change: plasma Aβ42/Aβ40, 0.014 standard deviations (95% confidence intervals 0.002 to 0.026); CSF Aβ42/Aβ40, 0.020 (0.008 to 0.032); plasma Nfl, −0.018 (−0.030 to −0.005); and CSF NfL, −0.024 (−0.036 to −0.012). Power analyses estimated that 266 individuals in each treatment arm would be needed to detect a 50% slowing of decline if identified by abnormal plasma measures versus 229 for CSF measures. Interpretation: Both plasma and CSF measures of Aβ42/Aβ40 and NfL predicted cognitive decline. A clinical trial that enrolled individuals based on abnormal plasma Aβ42/Aβ40 and NfL levels would require only a marginally larger cohort than if CSF measures were used. © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
National Institute on AgingNIAP01AG003991, P01AG026276, P30AG066444, R01AG053550, R01AG070941
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A flexible modeling approach for biomarker-based computation of absolute risk of Alzheimer’s disease dementia
(2022) Alzheimer’s and Dementia, .
Hartz, S.M.a , Mozersky, J.a , Schindler, S.E.a , Linnenbringer, E.a , Wang, J.a , Gordon, B.A.a , Raji, C.A.a , Moulder, K.L.a , West, T.b , Benzinger, T.L.S.a , Cruchaga, C.a , Hassenstab, J.J.a , Bierut, L.J.a , Xiong, C.a , Morris, J.C.a
a Washington University School of Medicine, St. Louis, MO, United States
b C2N Diagnostics, St. Louis, MO, United States
Abstract
Introduction: As Alzheimer’s disease (AD) biomarkers rapidly develop, tools are needed that accurately and effectively communicate risk of AD dementia. Methods: We analyzed longitudinal data from >10,000 cognitively unimpaired older adults. Five-year risk of AD dementia was modeled using survival analysis. Results: A demographic model was developed and validated on independent data with area under the receiver operating characteristic curve (AUC) for 5-year prediction of AD dementia of 0.79. Clinical and cognitive variables (AUC = 0.79), and apolipoprotein E genotype (AUC = 0.76) were added to the demographic model. We then incorporated the risk computed from the demographic model with hazard ratios computed from independent data for amyloid positron emission tomography status and magnetic resonance imaging hippocampal volume (AUC = 0.84), and for plasma amyloid beta (Aβ)42/Aβ40 (AUC = 0.82). Discussion: An adaptive tool was developed and validated to compute absolute risks of AD dementia. This approach allows for improved accuracy and communication of AD risk among cognitively unimpaired older adults. © 2022 the Alzheimer’s Association.
Author Keywords
return of research results; risk estimation; survival analysis
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Non-sedative cortical EEG signatures of allopregnanolone and functional comparators
(2022) Neuropsychopharmacology, .
Lambert, P.M.a b , Ni, R.a , Benz, A.a , Rensing, N.R.c , Wong, M.c , Zorumski, C.F.a d , Mennerick, S.a d
a Department of Psychiatry, Washington University in St. Louis School of Medicine, 660S. Euclid Ave., MSC 8134-0181-0G, St. Louis, MO 63110, United States
b Medical Scientist Training Program, Washington University in St. Louis School of Medicine, 660S. Euclid Ave., MSC 8134-0181-0G, St. Louis, MO 63110, United States
c Department of Neurology, Washington University in St. Louis School of Medicine, 660S. Euclid Ave., MSC 8134-0181-0G, St. Louis, MO 63110, United States
d Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis School of Medicine, 660S. Euclid Ave., MSC 8134-0181-0G, St. Louis, MO 63110, United States
Abstract
Neurosteroids that positively modulate GABAA receptors are among a growing list of rapidly acting antidepressants, including ketamine and psychedelics. To develop increasingly specific treatments with fewer side effects, we explored the possibility of EEG signatures in mice, which could serve as a cross-species screening tool. There are few studies of the impact of non-sedative doses of rapid antidepressants on EEG in either rodents or humans. Here we hypothesize that EEG features may separate a rapid antidepressant neurosteroid, allopregnanolone, from other GABAA positive modulators, pentobarbital and diazepam. Further, we compared the actions GABA modulators with those of ketamine, an NMDA antagonist and prototype rapid antidepressant. We examined EEG spectra during active exploration at two cortical locations and examined cross-regional and cross-frequency interactions. We found that at comparable doses, the effects of allopregnanolone, despite purported selectivity for certain GABAAR subtypes, was indistinguishable from pentobarbital during active waking exploration. The actions of diazepam had recognizable common features with allopregnanolone and pentobarbital but was also distinct, consistent with subunit selectivity of benzodiazepines. Finally, ketamine exhibited no distinguishing overlap with allopregnanolone in the parameters examined. Our results suggest that rapid antidepressants with different molecular substrates may remain separated at the level of large-scale ensemble activity, but the studies leave open the possibility of commonalities in more discrete circuits and/or in the context of a dysfunctional brain. © 2022, The Author(s).
Funding details
National Institute of Mental HealthNIMHHD103525, MH122379, MH123748, MH126548
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis
Document Type: Article
Publication Stage: Article in Press
Source: Scopus